Enrichment of the inositol 1,4,5-trisphosphate receptor/Ca2+ channels in secretory granules and essential roles of chromogranins

The high capacity, low affinity Ca(2+) storage protein chromogranins are marker proteins of secretory granules that contain the most Ca(2+) in secretory cells. Along with the abundantly expressed chromogranins, the IP(3)R/Ca(2+) channels, the major intracellular Ca(2+) channels, are also expressed in secretory granules the most. Chromogranins not only induce formation of secretory granules but also are suggested to produce the small IP(3)-sensitive nucleoplasmic Ca(2+) store vesicles in the nucleus. Chromogranins A (CGA) and B (CGB) also directly bind the IP(3)Rs and activate the IP(3)R/Ca(2+) channels at the intragranular pH 5.5. But at a near physiological pH 7.5 only CGB interacts with the IP(3)Rs due to stronger interaction of CGB for the IP(3)Rs, which is several orders of magnitude stronger than that of CGA, and activates the IP(3)R/Ca(2+) channels. Therefore, the CGB-IP(3)R coupling is proposed to play key roles in the IP(3)-mediated Ca(2+) signaling mechanisms in the cytoplasm through both secretory granules and the ER, and in the nucleus through the small IP(3)-sensitive nucleoplasmic Ca(2+) store vesicles. Chromogranin B is further suggested to participate in transcription control and to target secretory granule components, including the IP(3)Rs, to newly formed secretory granules. Defects in secretory granule-related functions are directly linked to major human diseases such as Alzheimer's disease, secretory cell cancers, cystic fibrosis, acute pancreatitis, and cardiac hypertrophy. Therefore, realization of secretory granules as the major intracellular Ca(2+) storage and control organelle in secretory cells promises to open new horizon in understanding the Ca(2+) storage, signaling, and control mechanisms throughout the biokingdom.